AU720483B2

AU720483B2 - New derivatives of phenoxyethylamine, a process for their preparation, their use as medicaments and pharmaceutical compositions containing them

Info

Publication number: AU720483B2
Application number: AU44636/97A
Authority: AU
Inventors: Denis Bigg; Marie-Odile Galcera
Original assignee: Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
Current assignee: Ipsen Pharma SAS
Priority date: 1996-09-27
Filing date: 1997-09-26
Publication date: 2000-06-01
Anticipated expiration: 2017-09-26
Also published as: DE69705316D1; PL188747B1; US6150417A; RU2181119C2; CA2267251A1; EP0929515A1; HUP9903928A3; NO991482L; JP2001503392A; US5998666A; ATE202335T1; NZ334622A; WO1998013337A1; DK0929515T3; MY128191A; IL128918A; TW415934B; IL128918A0; FR2753967B1; ES2160366T3

Description

New derivatives of phenoxyethylamine, a process for their preparation, their use as medicaments and pharmaceutical compositions containing them ligands may be useful for the treatment of anxiety, depression and hypertension (Brain 5-HTIA Receptors: Behavioural and Neurochemical Pharmacology; Editors C.T. Dourish, S. Ahlenius, P.H. Huston: Ellis Horwod LTD, Chischester (1987)).

It has also been shown that 5-HTIA ligands inhibit the secretion of gastric acid (D.C.

Evans, J.S. Gidda, Gastroenterology. 104, A76 (1993)), exhibit anti-emetic effects Okada, Y. Torii, H. Saito, N. Matsuki, Jpn. J. Pharmacol., 64, 109 (1994)) and act on the motility of the gastrointestinal system (Serotonin and Gastrointestinal Function, Editors T. S. Gaginella, J.J. Galligan; CRC Press, Boca Raton (1995)).

The present invention relates to new derivatives of phenoxyethylamine having a high affinity for the 5-HT,, receptor, processes for their preparation, pharmaceutical compositions containing them, and their use as medicaments, particularly as inhibitors of gastric acid secretion or as anti-emetics.

A subject of the invention is, therefore, products corresponding to general formula I H H AO C R I I O in which Ar represents a phenyl substituted by one or more substituents; R represents a hydrocarbon radical containing 1 to 10 carbon atoms chosen from linear or branched alkyl, or cycloalkyl radicals; and salts of said products.

F

0 'r c More particularly, a subject of the invention is the products corresponding to general formula I as defined above, characterised in that the substituent(s) which the phenyl radical represented by Ar may bear are chosen from the lower alkoxy, NRR,,

-NHC(O)R

3

-NHC(O)NR

4

R

5

-NHC(O)OR

6 radicals, in which R 3 R, and R represent, independently, a hydrogen atom or a lower alkyl, and R, represents a lower alkyl.

In the definitions given above, the expression lower alkyl represents preferably a linear or branched alkyl radical having 1 to 6 carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl and hexyl radicals.

The cycloalkyl radicals may be chosen from saturated monocyclic radicals having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radicals.

The lower alkoxy radicals may correspond to the lower alkyl radicals indicated above. Methoxy, ethoxy or isopropyloxy radicals are preferred.

The products corresponding to formula I may form addition salts with acids, particularly pharmacologically acceptable acids.

Examples of salts are given below in the experimental part.

A subject of the invention is in particular compounds corresponding to general formula I as described above, characterised in that Ar represents a phenyl radical substituted by a substituent chosen from the methoxy, -C(O)NHMe, -NHC(O)Me, NHCONH., -NHCONHMe, NHC(O)OMe radicals, and in that R represents the tertbutyl, neopentyl, cyclopentyl, cyclohexyl or cycloheptyl radical.

The substituents of the phenyl radical which Ar may represent are preferably 's1' situated in position 2 or 3.

Cn I More particularly, a subject of the invention is the products described below in the examples, particularly the products corresponding to the following formulae: N-tert-butyl -5-i [12-(2-methoxyphenoxy)ethyl I amino] pentanamide; N-cyclohexyl-5-[ 2-(2-methoxyphenoxy)ethyl I amino] pentanam ide; N-neopentyl-5-[ I2-(2-methoxyphenoxy)ethyl I amino] pentanamide; N-cyclopentyl -5-[1I2-(2-methoxyphenoxy)ethyl I amino] pentanamide;, N-cyclohepty {2-(2-methoxyphenoxy)ethy I I amino]lpentanamide; N-cyclohexyl-5-[ f 2- (methyl aminocarbonyl) phenoxy) ethyl amino]lpentanamide: N-neopentyl-5-[ 2 (methy lam inocarbonyl1) phenoxy) ethyl Iamino] pentanamide; N -neopenty1-5 [12- (am inocarbony lam ino) phenoxy) ethyl I Iamino] pentanamide; N-neopentyl (3-(am inocarbonylamni no) phenoxy) ethyl Iaminolpentanamide; N-cycloheptyl-5-[ {2-(3-(aminocarbonylamino)phenoxy)ethylIamino]lpentanam ide; N-cyclohexyl-5- (methylcarbonylamino) phenoxy)ethyl I amino] pentanamide; N -neopentyl1-5-1 (methylcarbonylam ino) phenoxy) ethyl)I aminolpentanamide; N- neopentyl [12- (methoxycarbonyl am ino) phenoxy) ethyl)I aminolpentanamide; N -neopentyl1-5 [12- (methyl am inocarbonyl) phenoxy) ethyl)I amino] butanamide; and the salts of said compounds with inorganic or organic acids.

The invention also provides a process for the preparation of products corresponding to general formula I as defined above, characterised in that 13) A) either a product corresponding to formula II

H

ArO in which Ar has the meaning given above, is allowed to react with a product corresponding to formula III 0

II

X/ C' OCH3 in which X represents a halogen or a pseudo halogen, in order to obtain a product corresponding to formula IV which product corresponding to formula IV is treated with an amine corresponding to the formula RNH 2 in which R has the meaning given above, in order to obtain a product corresponding to formula V

H

ArO CNN R 0 30 '4n I 1 which product corresponding to formula V is converted to a product corresponding to formula I by cleavage of the benzyl function, and which product corresponding to formula I may be converted to acid salts by the action of the corresponding acid.

B) or a product corresponding to formula VI

H

I

II

0 VI in which Y represents a halogen or pseudo halogen radical and R has the meaning given above is allowed to react with N-benzylethanolamine corresponding to the formula N O H

H

in order to obtain a product corresponding to formula VII

H

HO CN R

VII

0 which is converted to a product corresponding to formula VIII r H I R 0 Vll in which Z represents a halogen or pseudo halogen radical, which product corresponding to formula VIII is allowed to react with a compound corresponding to the general formula ArOH in which Ar has the meaning given above, in order to obtain a product corresponding to formula V as defined above, which product corresponding to formula V is converted to a product corresponding to formula I by cleavage of the benzyl function, and which product corresponding to formula I may be converted to acid salts by the action of the corresponding acid.

In the syntheses as presented above, X, Y and Z represent, independently, a leaving group such as chloro, bromo, iodo, methanesulfonyloxy, benzenesulfonyloxy or ptoluenesulfonyloxy, in other words, a halogen or pseudo halogen group.

The reaction of a compound corresponding to general formula II with a compound corresponding to general formula III in order to obtain a compound corresponding to general formula IV may be carried out easily by heating in a polar solvent, for example, acetonitrile or dimethylformamide, in the presence of an inorganic base such as potassium carbonate or sodium carbonate and optionally a catalyst such as potassium iodide.

The esters corresponding to general formula IV thus obtained may be converted to amides corresponding to general formula V by reaction with the corresponding amine by heating said two compounds, with reflux of the amine, without solvent, preferably under a nitrogen atmosphere or in an aromatic hydrocarbon in the presence of molecular sieve.

Depending on the substituents present on the phenyl radical which Ar represents, the Samides V may also be obtained after hydrolysis of the ester function and peptide I 0 i ^r /or -o coupling with the amines corresponding to general formula RNH 2 The amides corresponding to general formula V may also be obtained by reaction of sodium diethyldiaminoaluminates or of an amide complex of lithium and aluminium, prepared from amines corresponding to general formula RNH, according to known methods such as those described, for example, in Synlett. 10, 827-8 (1994) or in JL Org. Chem.. 57(22), 5831-4 (1992), with esters corresponding to general formula IV.

Compounds corresponding to general formula VII may be prepared by heating a compound corresponding to general formula VI with N-benzylethanolamine in a polar solvent such as an alcohol in the presence of an acid acceptor such as a tertiary amine or an inorganic base such as sodium carbonate or potassium carbonate.

Alternatively, compounds corresponding to general formula VII may be prepared easily by simply heating a compound corresponding to general formula VI with an excess of N-benzylethanolamine in the absence of a solvent, preferably under a nitrogen atmosphere and at a temperature between 60 0 C and 90 0

C.

The compounds corresponding to general formula VII thus obtained may be converted, for example, to chlorides corresponding to general formula VIII (Z=CI) by reaction with methanesulfonyl chloride in an inert solvent such as dichloromethane and in the presence of an organic base such as triethylamine or diisopropylethylamine.

Compounds corresponding to general formula V may be prepared from compounds corresponding to general formula VIII by reacting these latter with a phenoxide anion produced from the appropriate compound corresponding to formula ArOH, using a base such as sodium hydroxide, potassium hydroxide, or sodium hydride.

The reaction is carried out in an aprotic solvent and, preferably, in a dipolar aprotic solvent such as, for example, dimethylformamide.

The compounds corresponding to general formula I are obtained by deprotecting the compounds corresponding to general formula V according to general methods known to the person skilled in the art for debenzylation such as, for example,

C-

catalytic hydrogenation or the reaction with a chloroformate such as vinylchloroformate or a-chloroethylchloroformate followed by hydrolysis or methanolysis. Other methods of debenzylation as described in Protective Groups in Organic Synthesis Green, P.G.M. Wuts; 2nd Ed., J. Wiley and Sons Inc., p.

364-6 (1991)) may also be used provided they are compatible with the substituents on the aromatic nucleus of the compounds corresponding to general formula V.

Optional conversion to salts of the products corresponding to formula I is also carried out according to the usual methods indicated below in the experimental part.

The compounds of the present invention have advantageous pharmacological properties. It was thus discovered that the compounds of the present invention have a high affinity for the 5HT, receptor. The compounds of the present invention may thus be used in various therapeutic applications.

The compounds may inhibit the secretion of gastric acid. They may inhibit vomiting induced, for example, by cisplatin. Thus, the compounds of the invention may be used as anti-emetics or for the treatment of diseases in which it is necessary or desirable to reduce the secretion of gastric acid by, for example, gastric or duodenal ulcers, gastritis, gastro-oesophageal reflux, gastric dyspepsia, Zollinger-Ellison syndrome, nausea.

The compounds of the invention may also exhibit activity with respect to gastric emptying and intestinal motility. They may thus be used to combat constipation, post-operative atonia, gastroparesis.

They may also be used for the treatment of certain diseases of the nervous system such as anxiety, depression, sleep disorders such as insomnia, dependence on certain drugs, Alzheimer's disease, dizziness, eating disorders such as anorexia. The compounds of the invention may also be used to treat diseases of the cardiovascular system, particularly hypertension.

C

An illustration of the pharmacological properties of the compounds of the invention will be found below in the experimental part.

Said properties render the products corresponding to formula I suitable for pharmaceutical use. The present application also provides, as medicaments, the products corresponding to formula I as defined above, and the addition salts with pharmaceutically acceptable inorganic or organic acids of said products corresponding to formula I, and pharmaceutical compositions containing, as active principle, at least one of the medicaments as defined above.

The invention thus relates to pharmaceutical compositions containing a compound of S the invention or an addition salt of a pharmaceutically acceptable acid of the latter in combination with a pharmaceutically acceptable carrier. The pharmaceutical composition may be in the form of a solid, for example, powders, granules, tablets, capsules or suppositories. Suitable solid carriers may be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and wax.

The pharmaceutical compositions containing a compound of the invention may also be in the liquid form, for example, solutions, emulsions, suspensions or syrups.

Suitable liquid carriers may be, for example, water, organic solvents such as glycerol or glycols and mixtures thereof in various proportions in water, added to pharmaceutically acceptable oils or fats. The sterile liquid compositions may be used for intramuscular, intraperitoneal or subcutaneous injections, and the sterile compositions may also be administered intravenously.

The invention also provides the use of the products corresponding to formula I as defined above for the preparation of anti-emetic medicaments, medicaments intended to reduce gastric secretion, medicaments intended to accelerate gastric emptying, medicaments intended to modify intestinal transit, medicaments intended N)

S.-

-XN

to treat anxiety, depression, sleep disorders and medicaments intended to treat cardiovascular diseases.

The invention also provides, as new industrial products, and particularly as new industrial products intended for the preparation of products corresponding to formula 1, products corresponding to formulae IV, V, VII and VIII as described above.

The starting products of the invention, particularly the products corresponding to formulae II, III and VI, are known products or which may be prepared from known products. The following references may be cited: N-benzylethanolamine is a product sold, for example, by ACROS. The products corresponding to formula II may be 0 prepared by conventional methods from the corresponding phenoxyethylamines, for example, by way of benzamide followed by reduction by lithium aluminium hydride or an equivalent method. Alternatively, a reducing amination may be used according to the usual methods.

The phenoxyethylamines may be prepared according to the usual methods, for example, by reaction of a phenol with chloroacetonitrile in a basic medium, a reaction followed by reduction of the nitrile by lithium aluminium hydride according to the method described in Chim. Ther. 259-270 (1973).

The products corresponding to formula III are commercial products or may be produced by methods known to the person skilled in the art. Thus, the product corresponding to formula III, in which X represents a chlorine atom, is sold by

ACROS.

The products corresponding to formula VI may be prepared according to known methods from pentanoic acid, substituted in the 5 position by a halogen or a pseudo halogen, or activated derivatives such as the acid chloride or the activated ester, with which are reacted the amines corresponding to general formula RNHz.

2 rj

C

The phenolic derivatives corresponding to the general formula ArOH are commercial products or may be produced by methods known to the person skilled in the art.

The examples below are presented in order to illustrate the procedures above and should not in any case be regarded as limiting the scope of the invention.

EXPERIMENTAL PART: Example 1 0 N-cyclohexyl-5-[ 2-(2-methoxyphenoxy)ethyl} aminol pentanamide Ar 2-methoxyphenyl, R cyclohexyl: compound no. 2, Table 1) First step 12-(2-methoxyphenoxy)ethyl aminol pentanoate (IV, Ar 2-methoxyphenyl) Potassium carbonate (28.6 g, 0.21 mole) and potassium iodide (0.2 g, 1.2 mmole) are added to a solution of N-benzyl[2-(2-methoxyphenoxy]ethylamine hydrochloride (26.4 g, 0.09 mole) in dimethylformamide (100 ml). The reaction mixture is agitated for 10 minutes at 20°C, then a solution of methyl-5-chloropentanoate (15 g, 14.3 ml, 0.1 mole) in dimethylformamide (30 ml) is added dropwise. The mixture is agitated and heated to 60 0 C for 24 hours, then filtered and the solvent is evaporated under reduced pressure. The residue is taken up in dichloromethane (100 ml), washed with water (3 x 50 ml) and dried over magnesium sulfate. Filtration and evaporation of the solvent lead to an oil which is purified by flash chromatography over silica gel in a mixture of ethyl acetate/heptane 30 g of the desired compound are obtained.

4 0ij 0? NMR-'H (CDCI,, 6: 1.55-1.80 4H), 2.30 2H, J 8Hz), 2.60 2H, J 6 Hz), 2.92 2H, J 6 Hz), 3.66 3H), 3.69 3H), 4.07 2H, J 6 Hz), 6.80-6.95 (m, 4H), 7.20-7.40 Second step 2-(2-methoxyphenoxy)ethyl aminolpentanamide Ar 2-methoxyphenyl; R cyclohexyl) A solution of sodium diethyldihydroaluminate (4.44 ml, 8.9 mmole) in a concentration of 2 moles per litre in toluene, is added to a solution of cyclohexylamine (1.76 g, 2.03 ml, 18 mmole) in anhydrous toluene (60 ml). The reaction mixture is heated to 110 °C for 1 hour, then a solution of [benzyl{2-(2-methoxyphenoxy)ethyl}amino]pentanoate (6 g, 16 mmole) in toluene ml) is added dropwise. The mixture is heated under reflux for 3 hours and left for 18 hours at 20 then neutralised with a 10% solution of acetic acid. The organic phase is extracted then washed successively with a saturated solution of sodium hydrogen carbonate then with water. After drying over magnesium sulfate and evaporation of the solvents under reduced pressure, the product is purified by flash chromatography over silica gel in a mixture of ethyl acetate/heptane 3.3 g of the desired product are obtained in the form of an oil.

NMR-'H (CDC1 3 6: 1.00-1.80 14H), 2.10 2H, J 6.6 Hz), 2.60 2H, J 7.6 Hz), 2.90 2H, J 6 Hz), 3.67 2H), 3.85 3H), 4.08 2H, J 6 Hz), 6.80- 6.90 4H), 7.25-7.40 Third step 2-(2-methoxyphenoxy)ethyllaminolpentanamide (I,.Ar 2-methoxyphenyl, R cyclohexyl) A catalyst composed of palladium on 10% moist carbon (1.5 g) is added to a solution of N-cyclohexyl-5-[benzyl {2-(2-methoxyphenoxy)ethyl }amino]pentanamide (3 g, 6.8 mmole) in glacial acetic acid (30 ml) and the mixture is S hydrogenated for 2 hours at 20 OC. The catalyst is removed by filtration and the solvent is evaporated under reduced pressure. The residue obtained in the form of a salt of acetic acid is taken up in dichloromethane (50 ml) and the base is liberated by treatment with a saturated solution of sodium hydrogen carbonate. The organic phase is collected, washed with water, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The expected product is obtained in the form of a white powder after crystallisation in diethylether (0.95 g, The treatment of a solution of this free base (0.72 g) in ethanol under hot conditions with a hot ethanolic solution of fumaric acid (0.24 g) gives 0.8 g of compound no. 2 in the form of white crystals, m.p. 141.5-144 °C.

NMR-'H (DMSO), 6: 1.05-1.30 5H), 1.50-1.70 9H), 2.07 2H, J 6.6 Hz), 2.94 2H, J 6.9 Hz), 3.23 2H, J 5.3 Hz), 3.50 1H), 3.77 3H), 4.21 (t, 2H, J 5.3 Hz), 6.50 2H), 6.89-7.03 4H), 7.71 1H, J 7.8 Hz).

NMR-'

3 C (DMSO), 6: 22.81, 24.88, 25.31, 25.72, 32.78, 32.91, 35.07, 46.06, 47.30, 47.53, 55.53, 55.78, 65.52, 112.50, 114.74, 120.83, 121.00, 122.26, 135.02, 147.47, 149.58, 168.04, 170.88.

IR (Nujol), cm': 3278 1714 1635 1548 1577 741 (aromatic C-H).

Example 2 N-cyclcoheptyl-5-[12-(3-(aminocarbonylamino)phenoxy)ethyllaminolpentanamide Ar 3-(aminocarbonylamino)phenyl, R cycloheptyl: compound no. 10, Table 1) -v: /T First step N-cycloheptyl-5-lbenzyl(2-hydroxyethyl)aminolpentanamide (VII, R cycloheptyl) N-cycloheptyl-5-bromopentanamide (4.15 g. 15 mmole) in solution in dimethylformamide (20 ml) is added dropwise to a hot solution (60 of Nbenzylethanolamine (2.27 g, 2.13 ml, 15 mmole) in dimethylformamide (25 ml) in the presence of potassium carbonate (4.15 g, 3 mmole). The reaction mixture is agitated for 2 hours at 60 OC then the solvent is evaporated under reduced pressure.

The residue is taken up in dichloromethane (50 ml) and washed with water 3 x ml). The organic phase is collected, dried over magnesium sulfate; the solvent is evaporated under reduced pressure. The product obtained is purified by flash chromatography over silica gel in a mixture of dichloromethane/methanol (90/10) to give 3.04 g of the expected compound in the form of an oil.

Second step N-cycloheptyl-5-[benzyl(2-chloroethyl)aminolpentanamide (VIII, Z Cl, R cycloheptyl) Methanesulfonyl chloride (0.78 g, 0.52 ml, 6.6 mmole) is added dropwise with stirring to a cooled solution of N-cycloheptyl-5-[benzyl(2hydroxyethyl)amino]pentanamide (2.14 g, 6 mmole) in dichloromethane (20 ml) in the presence of triethylamine (0.69 g, 0.94 ml, 6.6 mmole). Agitation is maintained for 18 hours at 20 The reaction mixture is filtered with iced water (25 ml) then dried over magnesium sulfate. Filtration and evaporation of the solvent under reduced pressure give 2.2 g of the desired compound in the form of an oil.

NMR-'H (CDCI 3 6: 1.35-2.00 16H), 2.54 2H, J 6 Hz), 2.83 2H, J Hz), 2.95 2H, 5 Hz), 3.53 2H, J 6 Hz), 3.67 2H), 4.20 1H), 4.45 (m, 1H), 7.31 Third step 2-(3-(aminocarbonylamino)phenoxy)ethyl }amino] pentanamide Ar 3-(aminocarbonylamino)phenyl, R cycloheptyl) Potassium carbonate (0.92 g, 6.6 mmole) is added to a solution of 3hydroxyphenylurea (1 g. 6.6 mmole) in dimethylformamide (20 ml) and said mixture is stirred for 10 minutes at 20 0 C. A solution of N-cycloheptyl-5-[benzyl-(2chloroethyl)aminolpentanamide (2.21 g, 6 mmole) in dimethylformamide (20 ml) is then added dropwise, the mixture being kept under agitation for 4 hours at 80 °C.

The solvent is evaporated under reduced pressure, then the residue is taken up in 0 dichloromethane (50 ml) and washed with water. The organic phase is collected and dried then, after evaporation of.the solvent, the desired compound is obtained in the form of an oil. It is purified by flash chromatography over silica gel in a mixture of dichloromethane/methanol (95/5) to give 1.75 g of pure compound.

NMR-'H (CDCI 3 6: 1.30-1.90 16H), 2.12 2H, J 6 Hz), 2.53 2H, J 6 Hz), 2.80 2H, J 6 Hz), 3.63 2H), 3.95 1H), 4.07 2H, J 6 Hz), 4.93 (s, 1H), 5.55 1H), 6.68 2H), 7.19-7.30 9H).

SFourth step 2-(3-(aminocarbonylamino)phenoxy)ethyl i amino] pentanamide A catalyst composed of palladium on 10% moist carbon (0.3 g) is added to a solution of N-cycloheptyl-5-[benzyl {2-(3-aminocarbonylamino)phenoxy)ethyl amino]pentanamide (0.6 g, 1.2 mmole) in methanol (20 ml) and the mixture is hydrogenated for 24 hours at 20 The catalyst is then filtered and replaced by the same quantity. Hydrogenation is continued for another 24 hours. The catalyst is removed by filtration and the solvent is evaporated under reduced pressure. The desired product is obtained after purification by flash chromatography over silica gel in a mixture of dichloromethane/methanol/ammonia solution (90/10/1) (0.25 g, i i _r" 1 The treatment of a solution of this free base (0.11 g) in ethanol under hot conditions with a hot ethanolic solution of fumaric acid (33 mg) gives 0.14 g of compound no. 10 in the form of white crystals, m.p. 80-85 °C.

NMR-'H (DMSO), 6: 1.34-1.73 16H), 2.05 2H, J 6.4 Hz), 2.84 2H, J Hz), 3.18 2H, J 4.9 Hz), 3.70 1H), 4.11 2H. J 5.0 Hz). 5.97 2H), 6.48 2H). 6.87 1H. J 8.0 Hz), 7.11 1H, J 8.1 Hz), 7.28 1H), 7.73 (d, 1H,J 7.7 Hz), 8.84 IH).

IR (KBr), cm 3350 1700 1677 (urea), 1638 1590 1550 (C-N) The processes described above give a composition of the invention in the form of a free base or an addition salt with an acid. If the compound of the invention is obtained in the form of an addition salt with an acid, the free base may be obtained by converting a solution of the addition salt to a base with a base. Conversely, if the product of the process is a free base, the addition salt with an acid, particularly an addition salt with a pharmaceutically acceptable acid, may be obtained by dissolving the free base in an appropriate organic solvent and treating the solution with an acid, according to conventional procedures for the preparation of addition salts with an acid from free bases.

Examples of addition salts with an acid are those derived from inorganic acids such as sulfuric, hydrochloric, hydrobromic or phosphoric acid, or organic acids such as tartaric, fumaric, maleic, citric, caprylic, benzoic, methanesulfonic, ptoluenesulfonic, benzenesulfonic, succinic or acetic acid.

As regards the compounds of the invention containing an asymmetrical centre, the racemic mixtures and the individual optically active isomers are also considered to be part of the scope of the invention.

P) r i o-w 17 Table I below shows the main compounds prepared according to the above procedures and which illustrate the invention without limiting its scope. Compounds nos. 2 and 10 correspond respectively to the products of examples 1 and 2 described above. The other products were prepared using the same process.

Table I Compound Ar R Salt M.P. 1 2-MeO.CH, tert-butyl fumnarate 146-147 2 2-MeO.C 6 H, cyclohexyl fumarate 141.5-144 3 2-MeO.CH, neopentyl fumarate 128.5-131 4 2-MeO.C 6 H, cyclopentyl fumarate 128-129.5 2-MeO.C 6 H, cycloheptyl fumarate 131-134 6 2-MeNHC(O)C 6

H

4 cyclohexyl fumarate 126-129.5 7 2-MeNHC(O)C 6

H

4 neopentyl fumarate 143.5-145 8 2-H 2

NC(O)NH.C

6

H

4 neopentyl fumarate 153-154.5 9 3-HNC (0)NH.CH 4 neopentyl fumarate 150.5-152.5 3-H 2

NC(O)NH.C

6

H

4 cycloheptyl fumarate 81-85 11 3-MeC(0)NH.C 6

H

4 cyclohexyl hemnifumarate 176-177 12 3-MeC(O)NHC 6

H

4 neopentyl 0.75-fumarate 165.5-168.5 13 3-MeOC(0)NH.C 6

H

4 neopentyl fumarate 124.5-125 14 3-MeNHC(O)NHC 6

H

4 neopentyl fumarate 154.5-155.5 Using the process given above, it is also possible to prepare the following products, which are also part of the invention: -0I Compound Ar

R

A 3-MeO.C6H, ethyl B 3-EtO.CH, neopentyl C 3-MeO.C11 4 cyclohexyl D 2-NH,C(O)C 6 H. methyl E 2-NH 2

C(O).C

6

H

4 1 cyclopentyl F 2-MeNHC(O).C,H., cyclopentyl G 3-EtNHC(O)C 6 H, methyl H 2-(Me),NC(O).C 6

H

4 cycloheptyl I3-EtNHC(O)C 6 H, cycloheptyl J2-MeC(O)NH.C 6

H

4 neopentyl K 3-MeC(O)NHC 6

H

4 cyclopentyl L 3-EtC (O)NH.C 6

H

4 tert-butyl M 3-HC(O)NH.C 6

H

4 cyclopentyl N 2-H 2

NC(O)NH.C

6

H

4 cyclohexyl 0 2-MeNHC(O)NHC 6

H

4 neopentyl P 2-(Me) 2 NC(0)NH.C 6

H

4 cycloheptyl Q 3-MeNHC(O)NH.C 6 H, n-propyl R 3-EtNHC(0)NH.C 6

H

4 methyl S 2-MeOC(0)NH.C 6

H

4 neopentyl T 2-EtOC(0)N.C 6

H

4 cycloheptyl U 3-C 3

H

7 OC (0)NH.C 6

H

4 tert-butyl Pharmacological study of the products of the invention Affinity of the compounds of the invention for the 5-HTIA receptor The affinity of the compounds for serotonergic. 5-HTA receptors is determined by measuring the inhibition of [3H]8-hydroxy-2(di-n-propylaminotetral in ([3H118-OH- DPAT) bound to the cerebral cortex of the rat, according to the method of Peroutka and his coworkers [(J.Neurochem.. 47, 529 (1986)1.

Cerebral cortices of male Sprague Dawley rats are homogenised in Tris-HCI 50 mM, pH 7.4 and centrifuged at 40,000 g for 10 min at 4 Pellets are resuspended in the same buffer and incubated for 10 min at 37 and the homogenised products are centrifuged again at 40,000 g for 10 min at 4 °C.

Competitive inhibition tests of [3H]8-OH-DPAT binding are carried out three times with unlabelled competitors, with concentrations between 100 pM and 100 P[M.

Cerebral cortex membranes of rats (10 mg wet weight/ml) are incubated with [3H]8- OH-DPAT (InM) for 30 min at 25 °C in Tris-HCI 50 mM, pH 7.4 containing 4 mM of CaCI 2 10 tM of pargyline and 0.1% of ascorbic acid.

The bound [3H]8-OH-DPAT is separated from free [3H]8-OH-DPAT by immediate filtration by means of Whatman GF/B glass fibre filters using a Brandel cell recovery device. The filters are washed three times with the same buffer at 0-4 °C and their radioactivity is studied by means of a liquid scintillation spectrometer.

The specific binding is obtained by subtracting the binding determined in the presence of 1 1 iM of 8-OH-DPAT from the total binding. The characteristics of the binding are analysed by iterative analysis of the non-linear regression by computer, using the Ligand program [Munson and Rodbard, Anal. Biochem., 107, 220 (1980)].

The results for the compounds which are representative of the invention are given in Table 2 below.

7 ii Table 2 Compound no. Ki(nM) 1 0.54 2 0.19 3 0.32 4 0.29 0.098 9 0.41 0.13 11 0.37 12 0.88 13 0.84

''T

Claims

1. The compounds corresponding to general formula I H H 01 in which Ar represents a phenyl substituted by one or more substituents chosen from the lower alkoxy, -C(O)NR 1 -HNC(O)R,, -NHC(O)NR 4 -NHC(O)0R, radicals in which R 1 R 2 1 RV, R 4 and R. represent, independently, a hydrogen atom or a lower alkyl, and R. represents a lower alkyl; R represents a hydrocarbon radical containing 1 to 10 carbon atoms chosen from linear or branched alkyl, or cycloalkyl radicals; and salts of said products. The compounds corresponding to general formulalIas defined in claim 1, characterised in that Ar represents a phenyl radical substituted by a substituent chosen from the methoxy, -C(O)NHMe, -NHC(O)Me, -NHCONH

2 NHCONHMe, NHC(O)OMe radicals, and in that R represents the tert-butyl, neopentyl, cyclopentyl, cyclohexyl or cycloheptyl radical.

3. The compounds corresponding to general formula I as defined in one of claims 1 or 2 and corresponding to the following formulae: N-te rt-b utyl-5-[{2- meth oxyp hen oxy)ethyllam in o]pentanam ide; N-cyclohexyl-5-({2-(2-methoxyphenoxy)ethyl}amino]pentanamide; N- neopentyl-5-jI{2- (2-methoxyp hen oxy) ethyl) am i no]lpentan amid e; N-cyclopentyl-5-[{2-(2-methoxyphenoxy)ethyllamino]pentanamide; N-cycloheptyl-5-[{2-(2-methoxyphenoxy)ethyllamino]pentanamide; N-cyclohexyl-5-[{2-(2-(methylaminocarbonyl)phenoxy)ethyllamino] pentanamide; -N-neopentyl-5-[{2-(2-(methylami nocarbonyl) phen oxy) ethyllam ino) pentanamide; N-neopentyl-5-[{2-(2-(aminocarbonylamino)phenoxy)ethyllamino] pentanamide; N-neopentyl-5-[{2-(3- (am in ocarbonylam ino) phen oxy) ethyl)am ino] pentanamide; N-cycloheptyl-5-[{2-(3-(aminocarbonylamino)phenoxy)ethyllamino] pentanamide; N-cyclohexyl-5-[2-(3-(methylcarbonylamino)phenoxy)ethyllamino] pentanamide; N N-neope ntyl-5-[{2-(3- (methylcarbonylam ino) phen oxy) ethyllam ino] pentanamide; -N-neopentyl-5-[{2-(3-(meth oxycarbony lam ino) ph enoxy) ethyl~am ino] pentanamide; N-neopentyl-5-[{2- (methylam inocarbonyl) phen oxy)ethyllam in o] ad pentanamide; adthe salts of said compounds with inorganic or organic acids.

4. A process for the preparation of products corresponding to general formula I as defined in claim 1, characterised in that A) either a product corresponding to formula 11 H in which Ar has the meaning given in claim 1, is allowed to react with a product corresponding to formula Ill 0 x COCH 3 III in which X represents a halogen or a pseudo halogen, in order to obtain a product corresponding to formula IV ArO OCH3 II 0 IV which product corresponding to formula IV is treated with an amine corresponding to the formula RNH, in which R has the meaning given in claim 1, in order to obtain a product corresponding to formula V H /ArO R II O V B) or a product corresponding to formula VI H Y N C N R VI II o VI in which Y represents a halogen or pseudo halogen radical and R has the meaning given in claim I is allowed to react with N-benzylethanolamine corresponding to the formula SoI i H in order to obtain a product corresponding to formula VII which is converted to a product corresponding to formula VIII VIII in which Z represents a halogen or pseudo halogen radical, which product corresponding to formula VIII is allowed to react with a compound corresponding to the general formula ArOH in which Ar has the meaning given in claim 1, in order to obtain a product corresponding to formula V as defined above, which product corresponding to formula V is converted to a product corresponding to formula I by cleavage of the benzyl function, and which product corresponding to formula I may be converted to acid salts by the action of the corresponding acid.

Pharmaceutical compositions containing a product corresponding to formula I as defined in claim 1, and the additions salts with pharmaceutically acceptable inorganic or organic acids of the said products corresponding to formula I.

6. Pharmaceutical compositions containing a product corresponding to formula I as defined in one of claims 2 or 3, and the addition salts with pharmaceutically acceptable inorganic or organic acids of the said products corresponding to formula I.

7. The use of the products corresponding to formula I as defined in any one of claims 1 to 3 for the preparation of anti-emetic medicaments.

8. The use of the products corresponding to formula I as defined in any one of claims 1 to 3 for the preparation of medicaments intended to reduce gastric secretion. S

9. The use of the products corresponding to formula I as defined in any S: one of claims 1 to 3 for the preparation of medicaments intended to accelerate *SS° gastric emptying. ooo.

The use of the products corresponding to formula I as defined in any one of claims 1 to 3 for the preparation of medicaments intended to modify i intestinal transit. *.SS So..

11. The use of the products corresponding to formula I as defined in any one of claims 1 to 3 for the preparation of medicaments intended to treat anxiety, depression, sleep disorders. J- NL 1 J\ .DYV=;0~ 26

12. The use of the products corresponding to formula I as defined in any one of claims 1 to 3 for the preparation of medicaments intended to treat cardiovascular diseases, particularly hypertension.

13. The compounds corresponding for formulae IV, V, VII and VIII as defined in claim 4. DATED this 31' day of March 2000 SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES (SCRAS) WATERMARK PATENT AND TRADE MARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA LCG:RBP:VRH P7711AUOO.DOC *a 0* 00o* *a